Melt-extruded orally administrable opioid formulations

ABSTRACT

Bioavailable sustained release oral opioid analgesic dosage forms, comprising a plurality of multiparticulates produced via melt extrusion techniques are disclosed.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to the use of melt extrusiontechnology in the production of bioavailable sustained-release matrixpharmaceutical formulations. Previously, melt extrusion has been used inthe production of immediate release formulations.

[0002] It is known in the pharmaceutical art to prepare compositionswhich provide for controlled release of pharmacologically activesubstances contained in the compositions after oral administration tohumans and animals. Such slow release compositions are used to delayabsorption of a medicament until it has reached certain portions of thealimentary tract. Such sustained-release of a medicament in thealimentary tract further maintains a desired concentration of saidmedicament in the blood stream for a longer duration than would occur ifconventional rapid release dosage forms are administered.

[0003] Different methods of preparing controlled release pharmaceuticaldosage forms have been suggested. For example, direct compressiontechniques, wet granulation techniques, encapsulation techniques and thelike have been proposed to deliver pharmaceutically active ingredientsto the alimentary tract over extended periods.

[0004] Additionally, various types of sustained release formulations areknown in the art, including specially coated pellets, coated tablets andcapsules wherein the slow release of the active medicament is broughtabout through selective breakdown of the coating of the preparation orthrough compounding with a special matrix to affect the release of adrug. Some sustained release formulations provide for related sequentialrelease of a single dose of an active compound at predetermined periodsafter administration.

[0005] It is the intent of all sustained-release preparations to providea longer period of pharmacologic response after the administration ofthe drug and is ordinarily experienced after the administration of therapid release dosage forms. Such longer periods of response provide formany inherent therapeutic benefits that are not achieved withcorresponding short acting, immediate release preparations. This isespecially true in the treatment of cancer patients or other patients inneed of treatment for the alleviation of moderate to severe pain, whereblood levels of an opioid analgesic medicament must be maintained at atherapeutically effective level to provide pain relief. Unlessconventional rapid acting drug therapy is carefully administered atfrequent intervals to maintain effective steady state blood levels ofthe drug, peaks and valleys in the blood level of the active drug occurbecause of the rapid absorption, systemic excretion of the compound andthrough metabolic inactivation, thereby producing special problems inmaintenance of analgesic efficacy.

[0006] The prior art teaching of the preparation and use of compositionsproviding the sustained-release of an active compound from a carrier isbasically concerned with the release of the active substance into thephysiological fluid of the alimentary tract. However, it is generallyrecognized that the mere presence of an active substance in thegastrointestinal fluids does not, by itself, insure bioavailablity.

[0007] In order to be absorbed, the active drug substance must be insolution. The time required for a given proportion of an activesubstance frm a unit dosage form is determined as the proportion of theamount of active drug subsotance release from a unit dosage form over aspecified time base by a test method conducted under standardizedconditions. The physiological fluids of the gastrointestinal tract arethe media for determining dissolution time. The present state of the artrecognizes many satisfactory test procedures to measure dissolution timefor pharmaceutical compositions, and these test procedures are describedin official compendia world wide.

[0008] Although there are many diverse factors which influence thedissolution of drug substance from its carrier, the dissolution timedetermined for a pharmacologically active substance form the specificcomposition is relatively constant and reproducible. Among the differentfactors affecting the dissolution time are the surface area of the drugsubstance presented to the dissolution solvent medium, the pH of thesolution, the solubility of the substance in the specific solventmedium, and the driving forces of the saturation concentration ofdissolved materials in the solvent medium. Thus, the dissolutionconcentration of an active drug substance is dynamically modified in itssteady state as components are removed from the dissolution mediumthrough absorption across the tissue site. Under physiologicalconditions, the saturation level of the dissolved materials isreplenished form the dosage form reserve to maintain a relativelyuniform and constant dissolution concentration in the solvent mediumproviding for a steady stat absorption.

[0009] The transport across a tissue absorption site of thegastrointestinal tract is influenced by the Donnan osmotic equilibriumforces on both sides of the membrane since the direction of the drivingforce is the difference between the concentrations of active substanceon either side of the membrane, i.e., the amount dissolved in thegastrointestinal fluids and the amount present in the blood. Since theblood levels are constantly being modified by dilution, circulatorychanges, tissue storage, metabolic conversion and systemic excretion,the flow of active materials is directed from the gastrointestinal tractinto the blood stream.

[0010] Notwithstanding the diverse factors influencing both dissolutionand absorption of a drug substance, a strong correlation has beenestablished between the in-vitro dissolution time determined for adosage form and (in-vivo) bioavailablity. The dissolution time and thebioavailablity determined for a composition are two of the mostsignificant fundamental characteristics for consideration whenevaluating sustained=release compositions.

[0011] Metal granulations techniques have also been suggested to providecontrolled release formulations. Generally, melt granulation involvesmechanically working an active ingredient in particulate form with oneor more suitable binders and/or pharmaceutically acceptable excipientsin a mixer until one or more of the binders melts and adheres to thesurface of the particulate, eventually building up granules.

[0012] U.S. Pat. No. 4,957,681 (Klimesch, et. al.) discloses acontinuous process for preparing pharmaceutical mixtures having at leasttwo components which are continuously metered. The process includescontinuously metering the individual components of the pharmaceuticalmixture at a rate of at least 50 g/h on electronic differential meteringbalances having a metering accuracy of at least ±5% within timeintervals of less than one minute and, additionally, having screwconveyors, thereby obtaining a substantially uniformly metered mixture;and shaping the mixture. Example 1 of the '681 patent is representativeof the process. The requisite amounts of a copolymer having a K value of30 and obtained from 60% of N-vinylpyrrolid-2-one (NVP), stearyl alcoholand theophylline are metered via three metering balances into the hopperof an extruder and extruded. The temperatures of the extruder cylinderconsisting of six shots ranged form 30-60° C. and the die is heated to100° C. The resultant extrudate is then pressed into tablets of therequired shape. The '681 patent does not disclose preparation ofsustained release opioid pharmaceutical formulations.

[0013] N. Follonier., et al., Hot-Melt Extruded Pellets for theSustained Release of Highly Dosed Freely Soluble Drugs, Proceed. Intern.Symp. Control. Rel. Bioact. Mater., 18 (1991) described certaindiltiazem hydrochloride formulations prepared using hot-meltscrew-extrusion to obtain sustained-release pellets to be filled intohard gelatin capsules. The polymers used were ethylcellulose, acopolymer of ethyl acrylate and methyl methacrylate containingquaternary ammonium groups, cellulose acetate butyrate, poly(vinylchloride-co-vinly acetate) and a copolymer of ethylene and vinylacetate. In order to lower the extrusion temperature, some plasticizerswere used.

[0014] WO 93/07859 describes drug loaded pellets produced through meltspheronization wherein the therapeutically active agent is blended withvarious excipients and binders; the formulation is fed to an extruderwhere it is heated and extruded at a speed of about 0.05 to 10 mm/sec.at approximately 60-180° C. The extrudate is then cut into pieces in apelletizer and subsequently fed to a spheronizer for uniform pelletformulation.

[0015] Despite the foregoing advances and the various techniques forpreparing sustained release formulations available in the pharmaceuticalart, there is a need in the art for an orally administrable opioidformulation which would provide an extended duration of effect which isalso easy to prepare, e.g via melt-granulation techniques.

OBJECTS AND SUMMARY OF THE INVENTION

[0016] It is therefore an object of the present invention to providesustained-release pharmaceutical formulations suitable for oraladministration and methods for preparing the same utilizingmelt-extrusion techniques.

[0017] It is also an object of the present invention to provide improvedmethods for producing pharmaceutical extrudates containing opioidanalgesics and pharmaceutical acceptable hydrophobic materials via meltextrusion techniques.

[0018] It is a further object of the present invention to provide asustained-release melt extruded multi-particulate formulation which neednot be spheronized in order to obtain a final dosage form.

[0019] It is also an object of the present invention to provide methodsof treatment for human patients in need of opioid analgesic therapyusing dosage forms prepared in accordance with the methods disclosedherein.

[0020] In accordance with the above objects and others which will beapparent from the further reading of the specification and of theappended claims, the present invention is related in part to thesurprising discovery that sustained-release oral opioid analgesicformulations may be prepared utilizing melt extrusion techniques toprovide bioavailable unit dose products which provide analgesic in apatient for, e.g., 8-24 hours.

[0021] The invention is also related in part to a new melt-extruded oralsustained-release dosage forms which comprise a pharmaceuticallyacceptable hydrophobic material, a retardant selected from waxes, fattyalcohols, and fatty acids, and a drug.

[0022] More particularly, one aspect of the present invention is relatedto a pharmaceutical extrudate including an opioid analgesic dispersed ina matrix. Preferably, the extrudate is strand or spaghetti-shaped andhas diameter from about 0.1 to about 5 mm. The extrudate is divided intounit doses of the opioid analgesic for oral administration to a patient,and provides a sustained analgesic effect for 8-24 hours or more.

[0023] The matrices preferably include a hydrophobic material and asecond retardant material (preferably a hydrophobic fusible carrier)which acts to further slow or control the release of the therapeuticallyactive agent which the formulation is exposed to aqueous solutionin-vitro, or exposed to gastic and/or intestinal fluids.

[0024] Preferably, the hydrophobic material is selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil or hydrogenatedvegetable oil, or mixtures thereof.

[0025] The retardant material (hydrophobic fusible carrier) ispreferably selected from natural and synthetic waves, fatty acids, fattyalcohols and mixtures of the same. Examples include beeswax and carnaubawax, stearic acid, and stearyl alcohol. This list is of course not meantto be exclusive.

[0026] The extrudate may be cut into multiparticulates by any cuttingmeans known in the art. Preferably, the multiparticulates have a lengthof from about 0.1 to 5 mm in length. The multiparticulates may then bedivided into unit doses such that each individual unit dose includes adose of opioid analgesic sufficient to provide analgesia to a mammal,preferably a human patient.

[0027] The unit doses of multiparticulates may then be incorporated intoa solid pharmaceutical dosage formulation, e.g. via compression orshaping into tablets, by placing a requisite amount inside a gelatincapsule, or by forming the extruded product into the form of asuppository.

[0028] The pharmaceutical extrudates of the present invention may beprepared by blending the drug together with all matrix ingredients(hydrophobic material, binder and any additional (optional) excipients),feeding the resultant mixture into an extruder heated to the requisitetemperature necessary to soften the mixture sufficiently to render themixture extrudable; extruding the viscous, heated mass as aspaghetti-like strand; allowing the extrudate to congeal and harden, andthen dividing the strand into desired pieces. This may be accomplished,e.g., by cutting the strands into pellets of 1.5 mm in diameter and 1.5mm in length. Preferably, the extrudate has a diameter of from about 0.1and 5 mm and provides sustained release of said opioid analgesic for atime period of from about 8 to about 24 hours.

[0029] Another aspect of the invention is directed to pharmaceuticaldosage forms including the extrudate prepared as outlined above. Theextrudate is cut into multiparticulates using any cutting means known inthe art, e.g a blade. The multiparticulates are then divided into unitdoses containing an effective amount of opioid analgesic to provideanalgesia or pain relief in a human patient over the desired. dosinginterval. The unit dose of multiparticulates may then be incorporatedinto tablets, e.g. via direct compression, formed into suppositories, orencapsulated by any means known in the art.

[0030] In yet a further aspect of the invention, there is provided amethod of treating a patient with sustained-release formulationsprepared as described above. This method includes administering a dosageform containing the novel extrudate to a patient in need of opioidanalgesic therapy. For purposes of the present invention, a unit dose isunderstood to contain an effective amount of the therapeutically activeagent to produce pain relief and/or analgesia to the patient. Oneskilled in the art will recognize that the dose of opioid analgesicadministered to a patient will vary due to numerous factors; e.g. thespecific opioid analgesic(s) being administered, the weight andtolerance of the patient, other therapeutic agents concomitantly beingadministered, etc.

[0031] As mentioned above, in order for a dosage form to be effectivefor its intended purpose, the dosage form must be bioavailable. Forpurposes of the present invention, the term “bioavailable” is defined asthe total amount of a drug substance that is absorbed and available toprovide the desired therapeutic effect after administration of a unitdosage form. Generally, the bioavailablity of a given dosage form isdetermined by comparison to a known reference drug product, as commonlydetermined and accepted by Governmental Regulatory Agencies, such as theUnited States FDA.

[0032] The term “bioavailabity” is defined for purposes of the presentinvention as the extent to which the drug (e.g., opioid analgesic) isabsorbed from the unit dosage form and is available at the side of drugaction.

[0033] The terms “sustained release”, “extended duration”, and“controlled release” are defined for purposes of the present inventionas the release of the drug (e.g., opioid analgesic) at such a rate thatblood (e.g., plasma) levels are maintained within the therapeutic rangebut below toxic levels over a period of time greater than 8 hours, morepreferably for about 12 to about 24 hours, or longer.

[0034] The term “unit dose” is defined for purposes of the presentinvention as the total amount of multiparticulates needed toadministered a desired dose of therapeutically active agent (e.g.,opioid analgesic) to a patient.

[0035] The extrudates of the present invention preferably permit releaseof the opioid (or salts thereof) over a sustained period of time in anaqueous medium. The term “aqueous medium” is defined for purposes of thepresent invention as any water-containing medium, e.g. water,pharmaceutically acceptable dissolution medium, gastric fluid and/orintestinal fluid and the like.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The following drawing is illustrative of an embodiment of theinvention and is not means to limit the scope of the invention asencompassed by the claims.

[0037]FIG. 1 is a graph displaying the dissolution results of Examples 1and 2;

[0038]FIG. 2 is a graph displaying the dissolution rates of Example 3-6;

[0039]FIGS. 3 and 4 are graphs displaying the pH dependency of thedissolution results of Examples 3 and 6 respectively;

[0040]FIG. 5 is a graph displaying the dissolution results of Examples 7and 8 vs. Example 6;

[0041]FIG. 6 is a graph displaying the dissolution results of Examples 9and 10;

[0042]FIG. 7 is a graph displaying the dissolution results of Examples11 and 12;

[0043]FIG. 8 is a graph displaying the dissolution results of Examples15 and 16;

[0044]FIG. 9 is a schematic representation of a system for carrying outthe present invention;

[0045]FIG. 10 is a graph displaying the fed/fast bioavailablity resultsfor Example 20;

[0046]FIG. 11 is a graph displaying the plasma morphine concentrationsof Example 21 obtained form administration of the capsules from Example6 vs. MS Conti®;

[0047]FIG. 12 is a graph displaying the plasma oxycodone concentrationsof Example 22 obtained from administrating the capsules from Example 11and 13 vs. OxyConti®;

[0048]FIG. 13 is a graphical representation of the plasma oxycodoneconcentrations of Example 14;

[0049]FIG. 14 is a graphical representation of the hydromorphoneconcentrations of Example 24 using the capsules from example 17 vs.Dilaudid®;

[0050]FIG. 15 is a graph displaying the plasma hydromorphoneconcentrations of Example 24 using the capsules of Example 18 vs.Dilaudid®;

[0051]FIG. 16 is a graph of the steady-state plasma hydromorphoneconcentrations of Example 25 using the capsules of Example 17; and

[0052]FIG. 17 is a graph of the plasma hydromorphone concentrations ofExample 26 using the capsules of Example 19,

DETAILED DESCRIPTION

[0053] In one aspect of the invention, the sustained-release dosageforms comprise an opioid analgesic as the therapeutically active agent.In such formulations, the drug is incorporated into a melt-extrudedstrand which includes a pharmaceutically acceptable hydrophobic materialsuch as an alkylcellulose or an acrylic polymer or copolymer. In certainembodiments, it is preferably to further add to the blend a plasticizersfor the hydrophobic material in order to reduce the extrusiontemperature. The choice of the most suitable plasticizer is made basedon its ability to lower the glass transition temperature (Tg) of thepolymer. In preferred alternative embodiments, a hydrophobic fusiblecarrier (which may also act as a binder) is utilized instead of aplasticizer. The hydrophobic fusible carrier preferably imparts a slowerrelease of the therapeutically active agent form the melt extrudedformulation. Any further pharmaceutical excipients known to thoseskilled in the art may be added as deemed necessary.

[0054] Another aspect of the invention is directed to improved meltextruded matrices which comprise a hydrophobic material and a fattybinder such as previously specified. In accordance therewith, atherapeutically active agent is combined with one or more suitablehydrophobic materials and a hydrophobic fusible carrier is extruded toform an extrudate. The extrudate may then be cut into multiparticulateswhich are subsequently incorporated into sustained release dosage forms.

[0055] Therapeutically Active Agents

[0056] Therapeutically active agents which may be used in accordancewith the present invention include both water soluble and waterinsoluble drugs. Examples of such therapeutically active agents includeantihistamines (e.g., dimenhydrinate, diphenhydramine, chlorpheniramineand dexchlorpheniramine maleate), analgesics (e.g., asprin, codeine,morphine, dihydromorphone, oxycodone, et.), non-steroidalanti-inflammatory agents (e.g., naproxen, dichlofenae, indomethacin,ibuprofen, sulindac), anti-emetics (e.g., meloclopramide,methylnaltrexone), anti-epileptics (e.g., phentoin, meprobamate andnitrazepam), vasodilators (e.g., nifedipine, papaverine, dilitiazem andnicardipine), anti-tussive agents and expectorants (e.g., codeinephosphate), anti-asthmatics (e.g. theophylline), antacids,anti-spasmodics (e.g. atropine, scopolamine), antidiabetics (e.g.,insulin), diuretics (e.g., ethacrynic acid, bendrofluthiazide),anti-hypotensives (e.g., propranolol, clonidine), antihypertensives(e.g, clonidine, methyldopa), bronchodilators (e.g., albuterol),steroids (e.g., hydrocortisone, triamcinolone, prednisone), antibiotics(e.g., tetracycline), antihemorrhoidals, hypnotics, psychotropics,antidiarrheals, mucolytics, sedatives, decongestants, laxatives,vitamins, stimulants (including appetite suppressants such asphenylpropanolamine), as well as salts, hydrates, and solvents of thesame.

[0057] In embodiments of the invention directed to opioid analgesics,the opioid analgestics used in accordance with the present inventioninclude alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, cyclazocine, desomorphine, dextromoramide, dezocine,diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydrocodone, hydromophone,hydroxypethidine, isomethadone, ketobenidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, phopheptazine, promedol, properidine, propiram,propozyphenc, sufentanil, tramadol, tilidine, salts thereof, mixtures ofany of the foregoing, mixed mu-agonists/antagonists, mu-antagonistcombinations, and the like. The opioid analgesic may be in the form ofthe free base, or in the form of a pharmaceutically acceptable salt, orin the form of a pharmaceutically acceptable complex.

[0058] In certain preferred embodiments, the opioid analgesic isselected from morpine, codeine, hydromorphone, hydrocodone, oxycodone,dihydrocodeine, dihydromorphine, oxymorphone, tramadol or mixturesthereof.

[0059] In one preferred embodiment the sustained-release opioid oraldosage form of the present invention includes hydromorphone as thetherapeutically active ingredient in an amount from about 4 to about 64mg hydromophone hydrochloride. Alternatively, the dosage form maycontain molar equivalent amounts of other hydromorphone slats or of thehydromorphone base. In other preferred embodiments where the opioidanalgesic is other than hydromophone, the dosage form contains anappropriate amount to provide a substantially equivalent therapeuticeffect. For example, when the opioid analgesic comprises morphine, thesustained-release oral dosage forms of the present invention includefrom about 5 mg to about 800 mg morphine, by weight (based on morphinesulfate). When the opioid analgesic comprises oxycodone, thesustained-release oral dosage forms of the present invention includefrom about 5 mg to about 400 mg oxycodone. When the opioid analgesic istramadol, the sustained-release oral dosage forms of the inventioninclude from about 50 mg to about 800 mg tramadol by weight, based onthe hydrochloride salt.

[0060] The sustained-release dosage forms of the present inventiongenerally achieve and maintain therapeutic levels substantially withoutsignificant increases in the intensity and/or degree of concurrent sideeffects, such as nausea, vomiting or drowsiness, which are oftenassociated with high blood levels of opioid analgesics. There is alsoevidence to suggest that the use of the present dosage forms leads to areduced risk of drug addiction.

[0061] In the present invention, the oral opioid analgesics have beenformulated to provide for an increased duration of analgesic.Surprisingly, these formulations, at comparable daily dosages ofconventional immediate-release drug, are associated with a lowerincidence in severity of adverse drug reactions and can also beadministered at a lower daily dose than conventional oral medicationwhile maintaining pain control.

[0062] When the therapeutically active agent included in the dosageforms of the present invention is an opioid analgesic, the dosage formmay further include one or more additional which may or may not actsynergistically with the opioid analgesics of the present invention.Examples of such additional therapeutically active agents includenon-steroidal anti-inflammatory agents, including ibuprofen, diclofenac,naproxen, benoxaprofen, flubriprofen, fenoprofen, flubufen, ketoprofen,idoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acematacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the like.Other suitable additional drugs which may be included in the dosageforms of the present invention include acetaminophen, asprin,salicylate-derived analgesics and antipyretics or salts thereof, andother non-opioid analgesics.

[0063] The additional (non-opioid) therapeutically active agent may beincluded in control release form or in immediate release form. Theadditional drug may be incorporated into the controlled release matrixalong with the opioid; incorporated as a separated controlled releaselayer or immediate release layer; or may be incorporated as a powder,granulation, etc., in a gelatin capsule with the extrudates of thepresent invention.

[0064] Matrix Ingredients

[0065] The extrudates of the present invention include at lease onehydrophobic material. The hydrophobic material will preferably impartsustained release of the opioid analgesic to the final formulation.Preferred hydrophobic materials which may be used in accordance with thepresent invention include alkylcelluloses such as natural or syntheticcelluloses derivative (e.g. ethylcellulose), acrylic and methacrylicacid polymers and copolymers, shellac, zein, was-type substancesincluding hydrogenated castor oil or hydrogenated vegetable oil, ormixtures thereof. This list is not meant to be exclusive, and anypharmaceutically acceptable hydrophobic material which is capable ofimparting sustained release of the active agent and which melts (orsoftens to the extent necessary to be extruded) may be used inaccordance with the present invention.

[0066] In certain preferred embodiments of the present invention, thehydrophobic material is a pharmaceutically acceptable acrylic polymer,including but not limited to acrylic acid an methacrylic acidcopolymers, methyl methacrylate, methyl methacrylate copolymers,ethoxyethyl methacryaltes, cynaoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methancrylate copolymers.In other embodiments, the hydrophobic material is selected frommaterials such as hydroxyalkylcelluloses such ashydroxypropylmethylcellulose and mixtures of the foregoing.

[0067] The retardant material is preferably a hydrophobic fusiblecarrier which may comprise one or more water-insoluble wax-likethermoplastic substances possibly mixed with one or more wax-likethermoplastic substances being less hydrophobic than said one or morewater-insoluble was-like substances. In order to achieve constantrelease, the individual was-like substances in the binder materialshould be substantially non-degradable and insoluble in gastrointestinalfluids during the initial release phases.

[0068] Useful water-insoluble wax-like substances may be those with awater-solubility that is lower than about 1:5,000 (w/w).

[0069] Such hydrophobic fusible carrier materials are preferablywater-insoluble with more or less pronounced hydrophilic and/orhydrophobic trends. Preferably, the retardant materials useful in theinvention have a melting point from about 30 to about 200° C.,preferably from about 45 to about 90° C. Specifically, the hydrophobicfusible carrier may comprise natural or synthetic waxes, fatty alcohols(such as luryl, myristyl stearyl, cetyl or preferably cetostearylalcool), fatty acids, including but not limited to fatty acid esters,fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenatedfats, hydrocarbons, normal waxes, stearic aid, stearyl alcohol andhydrophobic and hydrophilic polymers having hydrocarbon backbones.Suitable waxes include, for example, beeswax, glycowax, castor was andcarnauba wax. For purposes of the present invention, a wax-likesubstance is defined as any material which is normally solid at roomtemperature and has a melting point of from about 30 to about 100° C.

[0070] Suitable hydrophobic fusible carrier materials which may be usedin accordance with the present invention include digestible, lone chain(C₈₋C₅₀, especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons,such as fatty acids, fatty alcohols, glyceryl esters of fatty acids,mineral and vegetable oils and natural and synthetic waxes. Hydrocarbonshaving a melting point of between 25° and 90° are preferred. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

[0071] In addition to the above ingredients, a sustained-release matrixmay also contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation. In addition to the above ingredients,a sustained-release matrix incorporating melt-extruded multiparticulatesmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the particulate if desired. Specific examplesof pharmaceutically acceptable carriers and excipients that may be usedto formulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (1986),incorporated by reference herein.

[0072] In order to facilitate the preparation of a solid,sustained-release oral dosage form according to this invention there isprovided, in a further aspect of the present invention, a process forthe preparation of a solid, sustained-release oral dosage form accordingto the present invention comprising incorporating opioids or a saltthereof in a sustained-release melt-extruded matrix. Incorporation inthe matrix may be effected, for example, blending the opioid analgesic,together with at least one hydrophobic material and preferably theadditional retardant material (hydrophobic fusible carrier) to obtain ahomogeneous mixture. The homogeneous mixture is then heated to atemperature sufficient to at least soften the mixture sufficiently toextrude the same. The resulting homogeneous mixture is then extruded,e.g., using a twin-screw extruder, to form strands. The extrudate ispreferably cooled and cut into multiparticulates by any means known inthe art. The strands are cooled and cut into multiparticulates. Themultiparticulates are then divided into unit doses. The extrudatepreferably has a diameter of from about 0.1 to about 5 mm and providessustained release of the therapeutically active agent for a time periodof from about 8 to about 24 hours.

[0073] An optional process for preparing the melt extrusion,multiparticulates and unit doses of the present invention includesdirectly metering into an extruder a water-insoluble retardant, atherapeutically active agent, and an optional binder; heating saidhomogeneous mixture; extruding said homogeneous mixture to thereby formstrands; cooling said strands containing said homogeneous mixture; andcutting said strands into particles having a size form about 0.1 mm toabout 12 mm; and dividing said particles into unit doses. In this aspectof the invention, a relatively continuous manufacturing procedure isrealized.

[0074] The diameter of the extruder aperture or exit port can also beadjusted to vary the thickness of the extruded strands. Furthermore, theexit part of the extruder need not be round; it can be oblong,rectangular, etc. The exiting strands can be reduced to particles usinga hot wire cutter, guillotine, etc.

[0075] The melt extruded multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded multiparticulate(s)” and “melt-extruded multiparticulatesystem(s)” and “melt-extruded particles” shall refer to a plurality ofunits, preferably within a range of similar size and/or shape andcontaining one or more active agents and one or more excipients,preferably including a retardant as described herein. In this regard,the melt-extruded multiparticulates will be of a range of from about 0.1to about 12 mm in length and have a diameter of from about 0.1 to about5 mm. In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size rangesuch as beads, microspheres, seeds, pellets, etc.

[0076] A particular advantage provided by the invention is thepreparation of sustained-release melt-extruded multiparticulateformulations which do not require further processing, e.g., theextrudate may simply be cut into desired lengths and divided into unitdoses of the therapeutically active agent without the need of aspheronization step.

[0077] In one preferred embodiment, oral dosage forms are prepared toinclude an effective amount of melt-extruded multiparticulates within acapsule. For example, a plurality of the melt-extruded multiparticulatesmay be placed in a gelatin capsule in an amount sufficient to provide aneffective sustained-release dose when ingested and contacted by gastricfluid.

[0078] In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

[0079] In yet another preferred embodiment, the extrudate can be shapedinto tablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et.al.), described in additional detail above and hereby incorporated byreference.

[0080] In yet a further embodiment, the extrudate can be shaped intosuppositories containing a unit dose of the therapeutically activeagent. This may be accomplished using techniques and equipment wellknown to those skilled in the art.

[0081] Optionally, the sustained-release melt-extruded multiparticulatesystem or tablets can be coated, or the gelatin capsule can be furthercoated, with a sustained-release coating comprising one of thehydrophobic materials described above. Such coatings preferably includea sufficient amount of hydrophobic material to obtain a weight gainlevel form about 2 to about 30 percent, although the overcoat may begreater depending upon the physical properties of the particular opioidanalgesic compound utilized and the desired release rate, among otherthings. In certain preferred embodiments of the present invention, thehydrophobic polymer comprising the sustained-release coating is apharmaceutically acceptable acrylic polymer, such as those describedherein above. The solvent which is sued for the hydrophobic material inthe coating may be any pharmaceutically acceptable solvent, includingwater, methanol, ethanol, methylene chloride and mixtures thereof.

[0082] The unit dosage forms of the present invention may furtherinclude combinations of melt-extruded multiparticulates containing oneor more of the therapeutically active agents disclosed above beforebeing encapsulated. Furthermore, the unit dosage forms can also includean amount of an immediate release therapeutically active agent forprompt therapeutic effect. The immediate release therapeutically activeagent may be incorporated, e.g., as separate pellets within a gelatincapsule, or may be coated on the surface of the compressed table whichhas been prepared from the multiparticulate extrudate as set forthabove.

[0083] The controlled-release formulations of the present inventionslowly release the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. Thecontrolled-release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofretardant, i.e., hydrophobic polymer, by varying the amount ofplasticizer relative to hydrophobic polymer, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture, etc. In certain embodiments of the invention, the thesustained-release dosage forms of the present invention preferablyrelease the therapeutically active agent at a rate that is independentof pH, e.g., between pH 1.6 and 7.2. In other embodiments, theformulations can be designed to provide a pH-dependent release of thetherapeutically active agent.

[0084] In other embodiments of the invention, the melt extruded materialis prepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate. Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tabletted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/or the retardant material.

[0085] Opioid Analgesic Formulations

[0086] In certain preferred embodiments, the invention is directed tosustained-release oral opioid formulations which are administrable on aonce-a-day basis, and which are prepared from the melt extrudatesdescribed herein. Such dosage forms will provide and in-vitro release(when assessed by the USP Paddle or Basket Method at 100 prm at 900 mlaqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 1 to about42.5% opioid released after one hour, from about 5 to about 65% opioidreleased after 2 hours, from about 15 to about 85% opioid released after4 hours, from about 20 to about 90% opioid released after 6 hours, fromabout 35 to about 95% opioid released after 12 hours, from about 45 toabout 100% opioid released after 18 hours, and from about 55 to about100% opioid released after 24 hours, by weight. Such formulations mayfurther be characterized by a peak plasma level at form about 2 to about8 hours after oral administration, and preferably from about 4 to about6 hours after administration. Such formulations are furthercharacterized by a W₅₀ from about 4 to about 12 hours.

[0087] In certain preferred embodiments, the oral 24 hoursustained-release opioid dosage form provides a rapid rate of initialrinse in the plasma concentration of the opioid after oraladministration, such that the peak plasma level obtained in-vivo occursfrom about 2 to about 8 hours after oral administration, and/or theabsorption half-life is from about 1 to about 8 hours after oraladministration (in the fasted state). More preferably in this embodimentthe absorption half-life is 1-6 hours and possibly 1-3 hours after oraladministration (in the fasted state). Such formulations provide anin-vitro dissolution under the conditions specified above, from about12.5 to about 42.5% opioid released after one hour, from about 25 toabout 65% opioid released after 2 hours, from about 45 to about 85%opioid released after 4 hours, and greater than about 60% opioidreleased after 8 hours, by weight.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

MELT-EXTRUSION TECHNIQUES

[0089] Typical melt extrusion systems capable of carrying-out thepresent invention include a suitable extruder drive motor havingvariable speed and constant torque control, start-stop controls, andammeter. In addition, the system will include a temperature controlconsole which includes temperature sensors, cooling means andtemperature indicators throughout the length of the extruder. Inaddition, the system will include an extruder such as twin-screwextruder which consists of two counter-rotating intermeshing screwsenclosed within a cylinder or barrel having an aperture or die at theexit thereof. The feed materials enter through a feed hopper and ismoved through the barrel by the screws and is forced through the dieinto strands which are thereafter conveyed such as by a continuousmovable belt to allow for cooling and being directed to a pelletizer orother suitable device to render the extruded ropes into themultiparticulate system. The pelletizer can consist of rollers, fixedknife, rotating cutter and the like. Suitable instruments and systemsare available from distributors such as C. W. Brabender Instruments,Inc. of South Hackensack, N.J. Other suitable apparatus will be apparentof those of ordinary skill in the art.

[0090] A further aspect of the invention is related to the preparationof melt extruded multiparticulates as set forth above in a manner whichcontrols the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, it has beensurprisingly found that the release rat of the therapeutically activeagent from the, e.g., multiparticulate extrudate, can be alteredsignificantly. In certain embodiments, it has been surprisingly foundthat the pH dependency of the extruded product can be altered as well.

[0091] A further aspect of the invention is related to the preparationof melt extruded multiparticulates as set forth above in a manner whichcontrols the amount of air included in the extruded product. Bycontrolling the amount of air included in the extrudate, it has beensurprisingly found that the release rate of the therapeutically activeagent form the, e.g., multiparticulate extrudate, can be alteredsignificantly. In certain embodiments, it has been surprisingly foundthat the pH dependency of the extruded product can be altered as well.

[0092] Thus, in a further aspect of the invention, the melt extrudedproduct is prepared in a manner which substantially excludes air duringthe extrusion phase of the process. This may be accomplished, forexample, by using a Leitritz extruder having a vacuum attachment. It hasbeen surprisingly found that extruded multiparticulates preparedaccording to the invention using the Leistritz extruder under vacuumprovides a melt-extruded product having different physicalcharacteristics. In particular, the extrudate is substantiallynon-porous when magnified, e.g., using a scanning electron microscopewhich provides an SEM (scanning electron micrograph). Contrary toconventional thought, it has been found that such substantiallynon-porous formulations provide a faster release of the therapeuticallyactive agent, relative to the same formulation prepared without vacuum.SEMs of the multiparticulates prepared using an extruder under vacuumappear very smooth, and the multiparticulates tend to be more robustthan those multiparticulates prepared without vacuum. It has beenobserved that in at least certain formulations, the use of extrusionunder vacuum provides an extruded multiparticulate product which is morepH-dependent than its counterpart formulation prepared without vacuum.

GENERAL PELLET MANUFACTURING PROCEDURE

[0093] The following technique was used to manufacture the extrudate andmultiparticulates for Examples 1-26.

[0094] Blend the required amount of drug, hydrophobic material andbinder along with any additional excipients.

[0095] Charge a powder feeder with proper amount of drug/excipientsblend.

[0096] Set temperatures of extruder heating zones to the requiredtemperature, depending on the formulation. Typically, the temperatureshould be set at about 83° C. Wait until the corresponding heat zonesreach steady temperatures. Set the extruder screw rotation speed to 20rpm. Start the feeder, the conveyor and the pelletizer. After theexcipients are melted and the drug is embedded in the molten mixture,the resultant viscous mass is extruded as spaghetti-like strands. Thediameter of the extruder aperture can be adjusted to vary the thicknessof the resulting strand.

[0097] Set the conveyor belt speed to an appropriate speed (e.g., 3-100ft/min). Allow the extruded semisolid strand(s) to be congealed and/orhardened while transported to the pelletizer on the conveyor belt.Additional cooling devices may be needed to ensure proper congealing.(The conveyor belt may not be needed to cool the strand, if the materialconceals rapidly enough.)

[0098] Set the roller knife to an appropriate speed (e.g., to 3-100ft/min and 100-800 rpm). Cut the congealed strands to desired size(e.g., 3-5 mm in diameter, 0.3-5 mm in length).

[0099] Collect the pellet product.

[0100] Fill a desired weight of pellets into hard gelatin capsules toobtain an appropriate doses of the drug.

DISSOLUTION METHOD

[0101] The following dissolution method was used to obtain dissolutionprofiles for the dosage forms of Example 1-25:

[0102] (USP 11 Paddle at 100 rpm at 37° C.)

[0103] Media—1st hour in 700 ml simulated gastric fluid (SGF), pH 1.2without enzyme thereafter, 900 ml simulated intestinal fluid (SIF), pH7.5 without enzyme

[0104] Using HPLC procedures for assay

[0105] The following examples illustrate various aspects of the presentinvention. They are not meant to be construed to limit the claims in anymanner whatsoever.

EXAMPLES 1-2 Controlled Release Chlorpheniramine Formulations

[0106] In these examples, chlorpheniramine maleate controlled releasepellets were prepared according to the above manufacturing procedureusing ethylcellulose and an acrylic polymer (Eudragit RSPO),respectively as the retardant. The formulations are set forth in Tables1 and 2 below. The dissolution of these formulations is set forth inFIG. 1. Drug release rate form ethylcellulose pellets (prepared at 105°C.) is significantly slower than that from Eudragit RSPO pellets(prepared at 85° C.). TABLE 1 EX. 1 Composition Amt. (mg) per CapsuleChlorpheniramine Maleate 60 Ethyl Cellulose 84 Stearic Acid 36 Total 180

[0107] TABLE 2 EX. 2 Composition Amt. (mg) per Capsule ChlorpheniramineMaleate 60 Eudragit RSPO 84 Stearic Acid 36 Total 180

EXAMPLES 3-6 Controlled Release Morphine Formulations

[0108] Ex.3 The excipients used in Ex. 2 were employed to make morphinesulfate controlled release pellets. TABLE 3 EX. 3 Composition Amt. (mg)per Capsule Morphine Sulfate 60 Eudragit RSPO 42 Stearic Acid 18 Total120

[0109] The drug release rate of Example 3 was slower than expectedespecially during later hours of the dissolution.

[0110] Ex. 4-5 Examples 4-5 were prepared in accordance with Example 3above. To increase the drug dissolution rate during later hours, varyingamounts of Eudragit L-100 were incorporated in the formulation. The drugdissolution rate increases with increasing amount of Eudragit L-100 inthe formulation. The morphine sulfate capsule formulation are set forthin tables 4-6 below: TABLE 4 EX. 4 Composition Amt. (mg) per CapsuleMorphine Sulfate 60 Eudragit RSPO 38.4 Eudragit L-100 3.6 Stearic Acid18 Total 120

[0111] TABLE 5 EX. 5 Composition Amt. (mg) per Capsule Morphine Sulfate60 Eudrigit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid 18 Total 120

[0112] Ex. 6. A sustained release morphine sulfate formulation wasprepared having the ingredients listed in Table 6 below: TABLE 6Percentage Ingredients Amt(mg)/Capsule in Formula Morphine Sulfate 60 50Eudragit RSPO 36 30 Eudragit L-100 6 5 Stearic Acid 18 15 Total 120 100

[0113] The formulation of Example 6 was prepared as follows:

[0114] Pellet Manufacture

[0115] a. Extruder system description. The twin screw extruder isconsisted of a pair of counter rotating screws and a barrel blockequipped with heating/cooling zones. The extrudate is delivered to apelletizer through a conveyor belt and cut into pellets of the desirablesize.

[0116] b. Manufacturing procedure.

[0117] 1. Blend the drug and all the excipients in a proper mixer.

[0118] 2. Place the mixture in a powder feeder.

[0119] 3. Set temperatures of the extruder heating zones toapproximately 83° C.

[0120] 4. Set the extruder screw rotation speed to 20 rpm.

[0121] 5. Start the feeder, the conveyor and the pelletizer.

[0122] 6. After the excipients are melted and the drug embedded in themolten mixture, the viscous mass is extruded as spaghetti-like strands.

[0123] 7. The extrudate is congealed and hardened while being deliveredto the pelletizer on the conveyor belt.

[0124] 8. The roller knife of the pelletizer cuts the strands intopellets of 1.5 mm in diameter and 1.5 mm in length.

[0125] Encapsulation

[0126] After the pellets were manufactured, 120 mg of pellets areencapsulated in size #2 heard gelatin capsules, rendering capsulescontaining 60 mg of morphine sulfate. These capsules were then testedusing the following dissolution methodology:

[0127] The capsules of Examples 6 were found to have the followingdissolution results: Time (hr)  1  2  4 8 12 18  24 Mean % dissolved 1633 52 72 84 95 102

[0128] As seen in FIG. 3, the drug dissolution rate obtained from theproduct of Ex. 3 showed a significant pH dependency. The release ratewas slower in SIF (simulated intestinal fluid) than in SGF (simulatedgastric fluid).

[0129] In FIG. 4, it can be seen that due to the addition of EudragitL-100, the drug dissolution rate obtained from Ex. 6 was less pHdependent. The drug release rate was faster in SIF during later hours ofdissolution which is desirable for complete bioavailablity.

EXAMPLES 7-8

[0130] As demonstrated in FIG. 5, with proper choice of plasticizers,the drug release rate from the formula containing Eudragit L-100 can bereduced. This may be necessary to achieve desirable plasma drugconcentration profiles after oral administration of the pellets. TABLE 7EX. 7 Composition Amt. (mg) per Capsule Morphine Sulfate 60 EudragitRSPO 33.6 Eudragit L-100 8.4 Stearic Acid 9 Diethyl Phthalate 9 Total120

[0131] TABLE 8 EX. 8 Composition Amt. (mg) per Capsule Morphine Sulfate60 Eudragit RSPO 33.6 Eudragit L-100 8.4 Stearic Acid 9 Tributyl Citrate9 Total 120

EXAMPLES 9-10

[0132] A different polymer/wax combination was used as a alternativeformulation. As seen in FIG. 6, the drug dissolution rate fromethylcellulose/polyvinyl acetate phthalate was somewhat faster. TABLE 9EX. 9 Composition Amt. (mg) per Capsule Morphine Sulfate 60 EthylCellulose 38.4 Polyvinyl Acetate Phthalate 3.6 Stearic Acid 18 Total 120

[0133] TABLE 10 EX. 10 Composition Amt. (mg) per Capsule MorphineSulfate 60 Ethyl Cellulose 34.8 Polyvinyl Acetate Phthalate 7.2 StearicAcid 18 Total 120

EXAMPLES 11-14 Controlled Release Oxycodone Formulations

[0134] The formula used in Ex. 6 was applied to oxycodone hydrochloride.Due to the higher potency of oxycodone, only 20 mg of drug was used. Themissing 40 mg was replaced by 40 mg of tale (Ex. 12). No replacement wasused in Ex. 11. When tested in only SGF or SIF, the use of Eudragit Lcauses the formulation to become less pH dependent. The results areshown in FIG. 7. TABLE II Percentage Ingredients Amt(mg)/Capsule inFormula Oxycodone HCL 20 25 Eudragit RSPO 36 45 Eudragit L-100  6 7.5Stearic Acid 18 22.5 Total 80 100

[0135] The pellet manufacturing procedure and the dissolution method arethe same as described in Example 6.

[0136] The above capsules were found to have the dissolution results setforth in Table 11a below: TABLE 11a Time (hr)  1  2  4 8 12 18  24 Mean% dissolved 14 29 45 66 81 94 101

[0137] TABLE 12 EX. 12 Composition Amt. (mg) per Capsule OxycodoneHydrochloride 20 Eudragit RSPO 36 Eudragit L-100  6 Stearic Acid 18 Talc40 Total 120 

[0138] Ex. 13 Oxycodone HCl once-a-day capsules were produced with thefollowing formula using the technology described in Example 6. Theformulation is set forth in Table 13 below. TABLE 13 PercentageIngredients Amt(mg)/Capsule in Formula Oxycodone HCl 20 25 Eudragit RSPO39 48.75 Eudragit L-100  3 3.75 Stearic Acid 18 22.5 Total 80 100

[0139] The pellet manufacturing procedure is the same as described inExample 6. However, 80 mg of pellets were encapsulated to contain 20 mgof oxycodone HCL.

[0140] The above capsules were tested using the following dissolutionmethodology:

[0141] 1. Apparatus—USP type II (paddle), 100 rpm at 37° C.

[0142] 2. Media—Either 900 ml simulated gastric fluid (SGF), pH 1.2without enzyme; or 900 ml simulated intestinal fluid (SIF), pH 7.5without enzyme.

[0143] 3. Analytical method—High performance liquid chromatography.

[0144] The dissolution results are set forth in Table 13a below: TABLE13a Time (hr)  1  2  4  8 12 18 24 Mean % dissolved (SGF) 13 20 29 41 5162 71 Mean % dissolved (SIF) 14 21 31 44 57 68 80

[0145] Ex. 14 To prepare an oxycodone HCl controlled release tabletwhich would dissolve preferentially in a lower pH, the following formulais used: TABLE 14 Ingredients Amt(mg)/Tablet Percentage in FormulaOxycodone HCl 40 30.8 Eudragit RS30D (solid) 14 10.8 Spray Dried Lactose35.25 27.1 PVP 5 3.9 Triacetin 2 1.5 Stearyl Alcohol 25 19.2 Talc 2.51.9 Magnesium Stearate 1.25 0.9 Film Coat 5 3.9 Total 130 100

[0146] Total Manufacture

[0147] 1. Mix Eudragit RS30D (suspension) and Triacetin for 5 minutes.

[0148] 2. Place spray dried lactose, oxycodone HCl, PVP, in a fluid beddrier.

[0149] 3. Spray the suspension onto the powders under fluidization.

[0150] 4. Pass the granulation though a Comil to reduce lumps.

[0151] 5. Melt stearyl alcohol at 70° C.

[0152] 6. Incorporate the molten stearyl alcohol into the drygranulation in a Collete Mixer.

[0153] 7. Transfer the waxed granulation to a cooling tray and allow thegranulation to congeal.

[0154] 8. Pass the granulation through a Comil.

[0155] 9. Mix the waxed granulation with tale and magnesium stearate ina Collete Mixer.

[0156] 10. Compress the lubricated granulation into tablets using arotary tablet press.

[0157] 11. Film coat the tablets.

[0158] These tablets were then tested using the following dissolutionmethodology described in Example 13.

[0159] The above tablets were found to have the following dissolutionresults: TABLE 14a Time (hr) 1 2 4 8 12 Mean % dissolved SGF 39 53 70 9099 Mean % dissolved SIF 35 48 65 83 93

EXAMPLES 15-19 Controlled Release Hydromorphone Formulations

[0160] Ex. 15-16 The formula used in Ex. 6 was applied to hydromorphonehydrochloride. Due to the higher potency of hydromorphone, only 8 mg ofdrug was used. The missing 52 mg was replaced by 52 mg of talc (Ex. 16)or 52 mg of excipients (Ex. 15). The results are shown in FIG. 8. TABLE15 EX. 15 Composition Amt. (mg) per Capsule Hydromorphone Hydrochloride8 Eudragit RSPO 67.2 Eudragit L-100 11.2 Stearic Acid 33.6 Total 120

[0161] TABLE 16 EX. 16 Composition Amt. (mg) per Capsule HydromorphoneHydrochloride  8 Eudragit RSPO 36 Eudragit L-100  6 Stearic Acid 18 Talc52 Total 120 

[0162] Ex. 17 Hydromorphone HCl once-a-day capsules were produced withthe formula set forth in Table 17 below using the technology describedin Example 6. TABLE 17 Percentage Ingredients Amt(mg)/Capsule in FormulaHydromorphone HCL  8 10 Eudragit RSPO 53 66.25 Stearyl Alcohol 19 23.75Total 80 100

[0163] The pellet manufacturing procedure is the same as describe dinExample 6. However, pellets of 1.0 mm in diameter and 1.0 mm in lengthwere prepared. Each capsule holds 80 mg of pellets and contains 8 mg ofhydromorphone HCL.

[0164] The above capsules were tested using the dissolution methodologydescribed in Example 6.

[0165] The above capsules were found to have the dissolution results setforth in Table 17a below: TABLE 17a Time (hr)  1  2  4  8 12 18 24 Mean% dissolved 17 28 32 45 56 69 82

[0166] Ex. 18 Hydromophone HCl once-a-day capsules were produced withthe formula set forth in Table 18 below as the second example of thetechnology described in Example 6. TABLE 18 Percentage IngredientsAmt(mg)/Capsule in Formula Hydromorphone HCl  8  10 Eudragit RSPO 48  60Stearyl Alcohol 24  30 Total 80 100

[0167] The pellet manufacturing procedure and the dissolution method arethe same as describe din Example 6.

[0168] The above capsules were found to have the dissolution results setforth in Table 18a below: TABLE 18a Time (hr)  1  2  4 8 12 18 24 Mean %dissolved 23 29 40 56 69 84 96

[0169] Ex. 19 Hydromorphone HCl once-a-day capsules were produced withthe following formula according to the method described Example 6. TABLE19 Percentage Ingredients Amt(mg)/Capsule in Formula Hydromorphone HCL 810 Eudragit RSPO 41.5 51.9 Eudragit L-100 8.5 10.6 Stearic Acid 22 27.5Total 80 100

[0170] The manufacturing procedure of the pellets and the dissolutionmethod are the same as described in Example 6.

[0171] The above capsules were found to have the following dissolutionresults: TABLE 19a Time (hr) 1  2  4  8 12 18 24 Mean % dissolved 4 1436 52 64 75 84

EXAMPLE 20

[0172] In this Example, a bioavailablity study was undertaken. Fourteensubjects were given the morphine sulfate formulations of Example 3. Theresults are provided in Table 20 below in FIG. 10. TABLE 20 Group AUCCmax Tmax Example 3 Fasted 230 15.7 2.1 Example 3 Fed 213 14.0 3.2

[0173] From the above data, it can be seen that the formulation is anideal candidate for an extended release or once-a-day product without afood effect.

EXAMPLE 21 Bioavailablity of morphine sulfate melt extrusionmultiparticulate 60 mg capsules

[0174] A bioavailablity study of morphine capsules of Example 6 wasconducted in 12 normal male volunteers. Capsules of 60 mg in strengthwere administered either with or without food in a single dose, two-waycrossover study. Blood samples were taken periodically and assayed formorphine concentrations using gas chromatography with mass detection(G/MS). From the data, the following pharmacokinetic parameters werecalculated and are indicated in Table 21 below. TABLE 21 AUC, Treatmentn · hr/ml Cmax, n/ml Tmax, hr Fasted 228 15.7 2.1 Fed 210 14.0 3.2

[0175] When compared to the typical blood levels of MS contin®, a singledose twice-a-day marketed morphine sulfate 30 mg tablets, in the fastedstate, it can be seen that the capsules of Example 6 are suitable foronce daily administration. At the 24th hour the blood levels are wellabove MS-Contin and within the therapeutic range (FIG. 11).

EXAMPLE 22 Bioavailablity of OXY-MEM 20 mg capsules.

[0176] A bioavailablity sturdy of oxycodone capsules of examples 11 and13 was conducted in 10 normal male volunteers. Capsules of example 13were administered either with or without food. Capsules of example 11were administered without food. The study was conducted in a singledose, four-way crossover design. Blood samples were taken periodicallyand assayed for oxycodone concentrations using gas chromatography withmass detection (G/MS).

[0177] From the data, the following pharmacokinetic parameters werecalculated as set forth in Table 22 below: TABLE 22 AUC, Treatment n ·hr/ml Cmax, n/ml Tmax, hr Example 13, fasted 207 9.7 5.3 Example 13, fed261 14.8 6.4 Example 11, fasted 244 12.9 6.0 Oxycontin, fasted 249 20.83.2

[0178] From the above data, it can be concluded that both Examples 11and 13, but particularly Example 13, are suitable for once dailyadministration. This is shown graphically in FIG. 12.

EXAMPLE 23 Bioavailablity of Example 14 Tablets

[0179] A bioabailability study of oxycodone controlled release tabletsof example 14 was conducted in 25 normal volunteers. These tablets wereadministered either with or without food. The study was conducted in asingle dose, randomized crossover design. Blood samples were takenperiodically and assayed for oxycodone concentrations using gaschromatography with mass detection (GC/MS). The plasma oxycodoneconcentration versus time curves are shown in FIG. 13.

[0180] From the data, the following pharmacokinetic parameters werecalculated. TABLE 23 Treatment AUC, ng · hr/ml Cmax, ng/ml Tmax, hrExample 14, fasted 422 39.3 3.1 Example 14, fed 416 35.3 4.8

[0181] Surprisingly, it was found that the controlled release oxycodoneHCl preparation, which dissolved preferentially in low pH, does not showsubstantial food effect. From the Cmax data, it can be seen that thereis no significant change in blood oxycodone levels when the drug wastaken with food than without food (35.3/39.3=0.09). From the AUC (areaunder the curve) data, it appears that the amount of drug absorbed withor without food is similar (416/422=0.986).

EXAMPLE 24 Bioavailablity of lllHH-MEM 8 mg capsules

[0182] A bioavailablity study of hydromorphone capsules of Examples 17and 18 was conducted using a single dose, five-way crossover study in 12normal male volunteers. The subjects received either 8 mg of Dilaudidtablet (immediate release) or 8 mg of lllHH-MEM capsules. Dilaudidtablets were administered after an overnight fast. MEM capsules wereadministered with or without food. Blood samples were taken periodicallyand assayed for hydromorphone concentrations using gas chromatographywith mass detection (G/MS). From the data, the following pharmacokineticparameters were calculated. TABLE 24 AUC, Treatment n · hr/ml Cmax, n/mlTmax, hr Example 17, fasted 19.00 0.72 6.8 Example 17, fed 20.10 0.752.4 Example 18, fasted 19.23 0.76 3.9 Example 18, fed 21.47 0.93 1.9Dilaudid, fasted 14.55 3.69 0.7

[0183] From the data, both formulations 17 and 18 would be suitable foronce-a-day administration both not having a food effect, and in factExample 17 looks ideal. The data of Example 17 is shown graphically inFIG. 14 and the data of Example 18 is shown graphically in FIG. 15.

EXAMPLE 25 Steady State Bioavailablity of lllHH-MEM 8 mg capsules

[0184] To assess steady state plasma levels and the effect of food onhydromorphone, a single dose, two-way crossover study was conducted in12 normal male volunteers. The subjects received either 4 mg of Dilaudid(immediate release) every 6 hours or 16 mg of the capsules according toExample 17 every 24 hours. Venous blood samples were taken atpredetermined time points. The plasma hydromorphone concentrations werequantitated using gas chromatography with mass detection (G/MS).

[0185] From the data from day 4, the following pharmacokineticparameters were calculated and are set forth in Table 25 below. TABLE 25AUC, Cmax, Treatment n · hr/ml n/ml Cmin, n/ml Tmax, hr Example 17 36.082.15 1.49 5.8 Dilaudid 33.53 3.44 0.94 1.6

[0186] The results are shown graphically in FIG. 16. From this data itcan be seen that Example 17 is an ideal product for once-a-dayadministration for either single dose or multiple dose administration.

EXAMPLE 26 Bioabailability of HH-MEM 8 mg capsules

[0187] To assess bioavailablity and effect of food on hydromorphone MEMcapsules, a single dose, three-way crossover study was conducted in 12normal male volunteers. The subjects received either 8 mg of Dilaudidtablet (immediate release) or 8 mg of HH-MEM (Example 19) Dilaudidtablets were administered after an overnight fast. MEM capsules wereadministered with our without food. Venous blood samples were taken atpredetermined at time points. The plasma hydromorphone concentrationswere quantitated using gas chromatography with mass detection (G/MS).

[0188] From the data, the following pharmacokinetic parameters werecalculated and are set forth in Table 26 below. TABLE 26 AUC, Cmax,Treatment n · hr/ml n/ml Tmax, hr Example 19, fasted 15.83 0.52 5.6Example 19, fed 16.55 0.65 4.1 Dilaudid, fasted 16.54 3.15 0.8

[0189] From the above data it can be concluded that a once-a-dayHydromorphone product can be produced using other ingredients than areused for Examples 17 and 18. This data is shown graphically in FIG. 17.

EXAMPLE 27 Tramadol HCl 200 mg SR Tablet

[0190] The following formula is used to prepare melt extrusiongranulation and tablet. TABLE 27 Percentage Ingredients Amt (mg)/Tabletin Formula Tramadol HCl 200 53.4 Eudragit RSPO 74 19.8 Tributyl Citrate14.8 4.0 Stearyl Alcohol 74 19.8 Talc 7.4 2.0 Magnesium Stearate 3.8 1.0Total 374 100

[0191] Granulation Manufacture

[0192] a. Extruder system description—The twin screw extruder isconsisted of a pair of counterrotating screws and a barrel blockequipped with heating/cooling zones. The stranded extrudate is congealedon a conveyor belt and cut into pellets of the desirable size.

[0193] b. Manufacturing procedure.

[0194] 1. Blend the drug and all the excipients in a proper mixer.

[0195] 2. Place the mixture in a powder feeder.

[0196] 3. Set temperatures of the extruder heating zones toapproximately 65° C.

[0197] 4. Set the extruder screw rotation speed to 40 rpm.

[0198] 5. Start the feeder and the conveyor.

[0199] 6. After the excipients are melted and the drug embedded in themolten mixture, the viscous mass is extruded as spaghetti-like strands.

[0200] 7. The extrudate is congealed and hardened while being carriedaway on a conveyor belt.

[0201] 8. The stranded extrudate was cut into pellets of 2 mm indiameter and 2-8 cm in length.

[0202] Tabletting

[0203] The pellets were milled into granules through a suitable screen.The granulation was blended with talc and magnesium stearate. Themixture was then compressed into capsule-shaped tablets.

[0204] Dissolution Method

[0205] 1. Apparatus—USP Type II (paddle), 100 rpm at 37° C.

[0206] 2. The tablet was placed in a tablet sinker clip and immersed ineach vessel.

[0207] 3. Media—900 ml pH 6.5 phosphate buffer.

[0208] 4. Analytical method—High performance liquid chromatography.

[0209] The above tablets were founded to have the following dissolutionresults: TABLE 27a Time (hr)  1  2  4  8 12 18 24 Mean % dissolved 24 3345 61 71 82 88

EXAMPLE 28 Tramadol HCl 200 mg SR Tablet

[0210] The following formula is used to prepare melt extrusiongranulation and tablet with a slower dissolution profile than Example27. TABLE 28 Percentage Ingredients Amt (mg)/Tablet in Formula TramadolHCl 200 44.1 Ethyl cellulose 110 24.3 Tributyl Citrate 22 4.9 StearylAlcohol 110 14.3 Talc 7.4 1.6 Magnesium Stearate 3.4 0.8 Total 453.2 100

[0211] The manufacturing procedure and dissolution method are the sameas described in Example 27. Additional dissolution media used include pH1.2 simulated gastric fluid (SGF) without enzyme, pH 7.5 simulatedintestinal fluid (SIF) without enzyme, and pH 4 phosphate buffer.

[0212] The above tablets were found to have the following dissolutionresults: TABLE 28a Time (hr) Mean % dissolved  1  2  4  8 12 18 24 SGF18 26 35 49 59 70 80 pH4 17 25 34 49 60 73 83 pH6.5 17 23 33 46 57 70 81SIF 17 23 32 45 56 68 78

[0213] The results show that the dissolution profiles of Tramadol SRtablets in media of different pH values are similar. Based on ourexperience with similar formula of other opiates, a formula whichdemonstrates pH independent dissolution profile would provide aconsistent drug release profile in vivo without food effect.

[0214] The examples provided above are not meant to be exclusive. Manyother variations of the present invention would be obvious to thoseskilled in the art, and are contemplated to be within the scope of theappended claims.

It is claimed:
 1. A sustained-release pharmaceutical formulation,comprising a melt-extruded blend of therapeutically active agent, one ormore hydrophobic materials selected from the group consisting ofalkylcellulose, acrylic and methacrylic acid polymers and copolymers,shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, andmixtures thereof; and one or more hydrophobic fusible carriers whichprovide a further retardant effect and selected from the groupconsisting of natural or synthetic waxes, fatty acids, fatty alcohols,and mixtures thereof, said hydrophobic fusible carrier having a meltingpoint from 30 to 200° C., said melt-extruded blend divided into a unitdose containing an effective amount of said therapeutically active agentto render a desired therapeutic effect and providing a sustained-releaseof said therapeutically active agent for a time period of from about 8to about 24 hours.
 2. The formulation of claim 1 , wherein saidextrudate comprises a strand-shaped matrix cut into multi-particulateshaving a length of from about 0.1 to about 5 mm in length.
 3. Theformulation of claim 1 , wherein said extrudate has a diameter of fromabout 0.1 to about 5 mm.
 4. The formulation of claim 1 , wherein saidtherapeutically active agent is an opioid analgesic.
 5. The formulationof claim 4 , wherein said opioid analgesic is selected from the groupconsisting of alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, cyclazocine, desomorphine, dextromoramide, dezocine,diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobenidone, levallorphan, levorphanol,levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papavercfum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, phopheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixturesthereof.
 6. The extrudate of claim 1 , wherein said opioid analgesic isselected from the group consisting of morphine, codeine, hydromorphone,hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine,tramadol and mixtures thereof.
 7. The formulation of claim 2 , wherein aunit dose comprising an effective amount of said multiparticulates torender a therapeutic effect is contained within a gelatin capsule. 8.The formulation of claim 2 , wherein a unit dose comprising an effectiveamount of said multiparticulates to render a therapeutic effect iscompressed into a tablet.
 9. The formulation of claim 8 , wherein saidtherapeutically active agent is tramadol.
 10. The formulation of claim 7wherein said therapeutically active agent is an opioid analgesicselected from the group consisting of morphine, codeine, hydromorphone,hydrocodone, oxycodone, oxymorphone, dihydrocodeine, dihydromorphine,tramadol and mixtures thereof.
 11. The formulation of claim 10 , whichprovides an in-vitro release (when assessed by the USP Paddle or BasketMethod at 100 prm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at37° C. from about 1 to about 42.5% opioid released after one hour, fromabout 5 to about 65% opioid released after 2 hours, from about 15 toabout 85% opioid released after 4 hours, from about 20 to about 90%opioid released after 6 hours, from about 35 to about 95% opioidreleased after 12 hours, from about 45 to about 100% opioid releasedafter 18 hours, and from about 55 to about 100% opioid released after 24hours, by weight.
 12. The formulation of claim 10 , which provides apeak plasma level at from about 2 to about 8 hours after oraladministration, and preferably from about 4 to about 6 hours afteradministration.
 13. The formulation of claim 10 , which provides a W₅₀from about 4 to about 12 hours.
 14. The formulation of claim 10 , whichprovides a rapid rat of initial rise in the plasma concentration of theopioid after oral administration, such that the peak plasma levelobtained in-vivo occurs from about 2 to about 8 hours after oraladministration.
 15. The formulation of claim 10 , which provides a rapidrat of initial rise in the plasma concentration of the opioid after oraladministration, such that the absorption half-life is from about 1 toabout 8 hours after oral administration (in the fasted state).
 16. Theformulation of claim 10 , which provides an in-vitro release (whenassessed by the USP Paddle or Basket Method at 100 prm at 900 ml aqueousbuffer (pH between 1.6 and 7.2) at 37° C. from about 12.5 to about 42.5%opioid released after one hour, from about 25 to about 65% opioidreleased after 2 hours, from about 45 to about 85% opioid released after4 hours, and greater than about 60% opioid released after 8 hours, byweight.
 17. The formulation of claim 1 , wherein said extruded blends issubstantially non-porous.
 18. A method preparing a sustained-releasepharmaceutical extrudate suitable for oral administration, comprising:blending a therapeutically active agent together with (1) a hydrophobicmaterial selected from the group consisting of alkylcelluloses, acrylicand methacrylic acid polymers and copolymers, shellac, zein,hydrogenated castor oil, hydrogenated vegetable oil, and mixturesthereof and (2) a hydrophobic fusible carrier selected from the groupconsisting of natural or synthetic waxes, fatty acids, fatty alcohols,and mixtures thereof, said retardant material having a melting pointbetween 30-200° C. and being included in an amount sufficient to furtherslow the release of the therapeutically active agent, heating said blendto a temperature sufficient to soften the mixture sufficiently toextrude the same; extruding said heated mixture as a strand having adiameter of from 0.1-3 mm; cooling said strand; and dividing said strandto form non-spheroidal multi-particulates of said extrudate having alength from 0.1-5 mm; and dividing said non-spheroidalmulti-particulates into unit doses containing an effective amount ofsaid therapeutically active agent, said unit dose providing asustained-release of said therapeutically active agent for a time periodof from about 8 to about 24 hours.
 19. The method of claim 18 , whereinsaid therapeutically active agent is an opioid analgesic is selectedform the group consisting of alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitranide, buprenorphine, butorphanol,clonitazene, codeine, cyclazocine, desomorphine, dextromoramide,dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobenidone, levallorphan, levorphanol,levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papavercium, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, phopheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine, salts thereof and mixturesthereof.
 20. The method of claim 18 , further comprising containing saidunit dose of said multiparticulates within a gelatin capsule.
 21. Themethod of claim 18 , further comprising compressing said unit dose ofmulti-particulates into a tablet.
 22. The method of claim 18 , furthercomprising extruding said heated mixture under vacuum conditions toprovide a substantially non-porous extrudate.
 23. A sustained-releasepharmaceutical formulation, comprising a melt-extruded blend of anopioid analgesic and one or more hydrophobic materials selected from thegroup consisting of alkylcelluloses, acrylic and methacrylic acidpolymers and copolymers, shellac, zin, hydrogenated castor oil,hydrogenated vegetable oil, and mixtures thereof; said melt-extrudedblend divided into a unit dose containing an effective amount of saidtherapeutically active agent to render a desired therapeutic effect andproviding a sustained-release of said therapeutically active agent for atime period of from about 8 to about 24 hours.
 24. The extrudate ofclaim 23 , wherein said opioid analgesic is selected from the groupconsisting of morphine, codeine, hydromorphone, hydrocodone, oxycodone,oxymorphone, dihydrocodeine, dihydromorphine, tramadol and mixturesthereof.